Globally, Helicobacter pylori (H. pylori) infects approximately 4.4 billion people, making it one of the most prevalent pathogens in humans (Hooi et al., 2017). H. pylori is a leading cause of chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma and gastric cancer, and plenty of researchers have emphasized the eradication of H. pylori infection to reduce these diseases (Lee et al., 2013; Graham et al., 2017). Moreover, H. pylori has also been suggested to be a risk factor for many extra-gastrointestinal diseases, such as cardiovascular diseases (de Korwin et al., 2017; Wang et al., 2017). Thus, H. pylori eradication is important for public health. However, the widespread use of antibiotics has led to a rise in antimicrobial resistance, which has decreased the cure rate for H. pylori infections (Megraud et al., 2021).

Traditional therapy for infectious disease depends on local, regional, or patient-specific antimicrobial susceptibilities (Graham and Dore, 2016), and susceptibility-guided treatment should be the best strategy if available. The currently recommended first-line H. pylori therapy in China is bismuth quadruple therapy (Liu et al., 2018). One study reported that rates of H. pylori resistance in China for clarithromycin, metronidazole, and levofloxacin were 35.1, 82.7, and 46.9%, respectively (Chen et al., 2019). Due to China’s high antibiotic resistance rates, treatment regimens have become increasingly complex. Personalized treatments based on antibiotic susceptibility represent a novel therapeutic option. However, susceptibility testing of H. pylori is difficult to perform and not practical in many clinical setting. As the resistant rate of amoxicillin and furazolidone remains low, the bismuth quadruple therapy containing these two medicines has been proved to be effective in China (Qiao et al., 2021). Besides, randomized controlled trials have shown that a bismuth quadruple therapy containing tetracycline remained highly effective (Chen et al., 2016), while tetracycline is difficult to obtain in many areas including China. Fortunately, several studies have proved the efficacy of minocycline in H. pylori eradication, which is a tetracycline derivative (Song et al., 2016).

Here, we conducted a study to assess the resistance of drugs used in H. pylori eradication, and to compare the efficacy of susceptibility-guided therapy (containing clarithromycin or minocycline according to susceptibility testing) with empiric therapy containing furazolidone.

Patients with H. pylori infection were randomly assigned to either 10-day susceptibility-guided treatment or empiric treatment in a 2:1 ratio. Technicians performing culture, antimicrobial susceptibility testing or urea breath test were blinded to treatment allocation. Patients in the empiric therapy was treated with furazolidone 100 mg twice daily for 10 days. Susceptibility-guided therapy was according to susceptibility to clarithromycin, and patients with susceptible strains received clarithromycin 500 mg twice daily and otherwise minocycline 100 mg twice a day was administered. During treatment, all patients were given esomeprazole 20 mg twice daily, colloidal bismuth pectin 200 mg twice daily, and amoxicillin 1 g twice daily.

At least 4 weeks after therapy completion, ¹³C- or ¹⁴C-urea breathe test was performed to assess H. pylori eradication, and negative urea breath test result was defined as eradication.

A total of 248 H. pylori-infected patients were evaluated for eligibility, and 47 met exclusion criteria or declined to participate and were excluded. Finally, 201 patients were enrolled and divided into furazolidone group (n = 67) and susceptibility-guided therapy group (n = 134) (as shown in Figure 1). The mean age was 42.5 for furazolidone group and 45.0 for susceptibility-guided therapy group (p = 0.180) (Table 1). There were 28 males in furazolidone group (41.8%) and 59 males in susceptibility-guided therapy group (44.0%) (p = 0.760) (Table 1). Overall, 15 patients were lost to follow-up UBT and five patient had poor compliance (four both had poor compliance and lost to follow-up), which were defined as treatment failure in the ITT analysis and were not included in the PP analysis. A total of 185 patients were finally included in the PP analyses (Figure 1).

In the current study including 201 patients, the resistant rate of metronidazole was high (70.0%), followed by clarithromycin (31.7%) and levofloxacin (29.5%), while the resistant rate was low for furazolidone (2.2%), tetracycline (1.6%), and amoxicillin (0%). The resistant rate of metronidazole and clarithromycin appeared to be higher than a previous study conducted in Korea, which suggested that resistant rate of metronidazole and clarithromycin was 29.5 and 17.8%, respectively (Lee et al., 2019). However, the resistant rate was similar with another study performed in China, of which the resistance rates of H. pylori for clarithromycin, levofloxacin, metronidazole, amoxicillin, and furazolidone were 26.12, 28.69, 96.79, 0, and 0%, respectively (Pan et al., 2020). The high rates of resistance to antibiotics have significantly reduced eradication rate of H. pylori (Sugano et al., 2015; Liu et al., 2018). As reported, traditional therapy eradication rate for H. pylori is below 80% in many cities, especially in high-risk areas for antibiotic resistance (Graham et al., 2014; Sebghatollahi et al., 2018).

Theoretically, therapy basing on the results of susceptibility testing for infectious diseases should be recommended, which is associated with higher efficacy, fewer side effects and unnecessary antibiotic use. According to the Maastricht V/Florence Consensus Report, susceptibility-guided therapy has been recommended after the second-line treatment fails (Malfertheiner et al., 2017). In a previous meta-analysis, tailored therapy was found to be more effective than empirically chosen treatment for eradicating H. pylori (Gingold-Belfer et al., 2021). The meta-analysis included both first-line and rescue treatments, and the role of susceptibility-guided therapy in first-line H. pylori remains unclear. Several studies suggested higher efficacy of susceptibility-guided therapy compared with empirically chosen treatment, while other studies found inconsistent results. Besides, the availability, accuracy, and cost-effectiveness of susceptibility-guided therapy should be considered in the clinical practice of H. pylori eradication (Matsumoto et al., 2019).

As a nitrofuran antibiotic, furazolidone damages bacterial DNA and interferes with normal bacterial metabolism. The primary and secondary resistance to furazolidone is low for H. pylori, and quadruple therapy containing furazolidone has been widely used in China (Xie et al., 2018). According to guidelines, furazolidone is recommended for eradication of H. pylori due to the low resistance (Malfertheiner et al., 2017; Liu et al., 2018). A number of studies have explored the efficacy and safety for rescue therapy and for naïve H. pylori-infected patients (Fakheri et al., 2001; Liang et al., 2013; Qiao et al., 2021). As reported by Liang et al. (2013) treatment regimens containing furazolidone were significantly more effective than treatments without furazolidone in rescue therapy of H. pylori. Another study compared clarithromycin with furazolidone for naïve H. pylori-infected patients, and recommended furazolidone-based quadruple therapy because of the high eradication rate, excellent cost-effectiveness and acceptable safety (de Korwin et al., 2017). In China, bismuth potassium citrate, colloidal bismuth pectin, and colloidal bismuth subcitrate are widely available. Currently, bismuth-containing quadruple therapy is the first-line treatment for H. pylori infection because it is effective against both susceptible and resistant strains (Malfertheiner et al., 2017; Liu et al., 2018).

In the current study, we compared the efficacy of susceptibility-guided therapy with empirical quadruple therapy containing furazolidone and bismuth, and both PP and ITT analyses suggested that these two therapies were comparable (90.5% in the furazolidone group and 88.5% in the susceptibility-guided therapy group for PP analysis; 85.1% in the furazolidone group and 80.6% in the susceptibility-guided therapy group for ITT analysis). Moreover, in the susceptibility-guided therapy group, no significant difference was found between clarithromycin group and the minocycline group. We observed a low rate of adverse effects for both furazolidone group (7.5%) and the susceptibility-guided therapy group (6.7%), and no severe adverse effects were found. The results further supported the use of furazolidone and minocycline in H. pylori eradication, and supported quadruple therapy containing furazolidone and bismuth when susceptibility test was unavailable.

There were several limitations in the current study. First, this was a single-center randomized controlled trial, which may limit generalizing the results. Second, obtaining tetracycline and minocycline remains difficult in many areas of China. Third, routinely performing H. pylori antimicrobial susceptibility test is difficult in most areas, which limits the use of susceptibility-guided therapy.

In conclusion, both susceptibility-guided therapy and empirical quadruple therapy containing furazolidone can achieve good eradication rates. For population with a high rate of resistance, empirical quadruple therapy containing furazolidone and bismuth may be a more practical choice for first-line treatment.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University, School of Medicine. The patients/participants provided their written informed consent to participate in this study.

YH and PL designed and conceived this study, and prepared for the manuscript. JJ, YC, and JM collected clinical samples and performed the experiments. QD, YH, and PL analyzed the data. All authors contributed to the article and approved the submitted version.